Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human heart failure is associated with a diminished contractile response to beta-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (alpha G40) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (Gs). The increased activity in alpha G40 was associated with a 30% decrease in basal as well as 5'-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased alpha G40 activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to beta 1-adrenergic agonists in the failing human heart.
 ...
PMID:Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. 283 45

The oxidative phosphorylation as well as calcium transporting properties of heart mitochondria and calcium transport activities of the fragments of the sarcoplasmic reticulum (microsomes) were studied during the life span of cardiomyopathic hamsters (UM-X7.1). Control healthy hamsters of the same age group were used for comparison. No changes in the oxidative phosphorylation ability of cardiomyopathic mitochondria were seen at early and moderate stages of heart failure; however, at severe stages, mitochondrial respiratory functions, but not the ADP:0 ratio, were impaired. Both creatine phosphate and ATP contents were decreased without any significant changes in the ATPase activities of myofibrils from the failing hearts. Heart mitochondria from cardiomyopathic animals at severe stages of failure exhibited less calcium binding and uptake activities in comparison with the control values whereas no changes in the mitochondrial calcium binding and uptake were seen in cardiomyopathic hamsters which showed no clinical signs of heart failure. Although mitochondrial calcium binding in cardiomyopathic hearts at early and moderate stages of failure was decreased, mitochondrial calcium uptake was not significantly different from the control. Microsomal calcium binding activity, unlike calcium uptake activity, was decreased in the hearts of cardiomyopathic hamsters without any signs of heart failure. Both calcium binding and calcium uptake activities of microsomes from animals with early, moderate and severe heart failure were less in comparison with the control values but were not associated with any changes in the Ca2+-stimulated ATPase activity. These results suggest that changes in the process of mitochondrial energy production and mitochondrial Ca2+-transport may be secondary to other factors whereas alterations in the sarcoplasmic reticular Ca2+-transport may lead to the development of heart failure in the cardiomyopathic hamsters.
 ...
PMID:Impairment of mitochondrial and sarcoplasmic reticular functions during the development of heart failure in cardiomyopathic (UM-X7.1) hamsters. 294 28

There is a decrease in total adenine nucleotides, cyclic AMP (cAMP), ATP/total ADP, and phosphocreatine (PCr)/creatine (Cr) both in situ and in the perfused heart in the heart failure stage of the cardiomyopathic Syrian hamster. There were decreases in developed pressure, dP/dt, and O2 consumption associated with the decrease in total adenine nucleotides and cAMP. Cardiomyopathic Syrian hamsters (180-240 days old) with congestive heart failure were given water with the calcium entry blocker, verapamil, as an additive 2 mo before death. In the cardiomyopathic group given verapamil the adenine nucleotides, cAMP, and high-energy phosphates were preserved and cardiac performance was not significantly different from that of the verapamil-treated healthy hamsters at the time of death. Pretreatment of cardiomyopathic animals with verapamil (6.6 mg verapamil/ml water consumed by drinking) resulted in significantly higher ATP/total ADP and PCr/Cr compared with nontreated cardiomyopathic hamsters. This is the first report demonstrating that a calcium entry blocker may improve cardiac performance and preserve total adenine nucleotides during the heart failure stage of the cardiomyopathic hamster.
 ...
PMID:Verapamil preserves adenine nucleotide pool in cardiomyopathic Syrian hamster. 394 35

A clinically relevant model of heart failure has been developed in chronically instrumented mini-pigs by injecting Sephadex beads into the left main or circumflex coronary arteries under fluoroscopic control. In six control animals, left atrial pressure (LAP) increased from 10 +/- 2 to 19 +/- 2 mmHg (p less than 0.01) and remained elevated for 3 days. Heart rate increased by 26 beats X min-1 (p less than 0.05) and diastolic pressure fell after 24 h but recovered over the next 48 h. In six animals treated with ticlopidine (50 mg X kg-1 p.o.) for four days prior to embolisation, the acute haemodynamic changes were less in the first day but similar to control after 3 days. Infarct size was approximately 20% of the left ventricle in control animals and 9.5% in the treated group (p less than 0.01). ADP-induced platelet activity was reduced in the treated animals suggesting that coronary occlusion followed both physical occlusion by the beads and later development of platelet thrombi.
 ...
PMID:A clinically relevant model of heart failure: effects of ticlopidine. 400 94

The development of myocardial infarction was shown to be accompanied by a rise in blood cAMP, cGMP and AMP levels, cyclic nucleotides peaking within the first hours of the disease. The increase in plasma cAMP, associated with developing heart failure, was more persistent. The administration of GIP mixture during the acute phase of myocardial infarction was conducive to lowering the levels of cyclic nucleotides and AMP, and raising blood ATP and ADP values. Clinically, the effect of GIP was manifested in reduced ventricular arrhythmias and diminished signs of heart failure.
 ...
PMID:[Effect of a glucose-insulin-potassium mixture on the cyclic and adenine nucleotide levels in the acute period of myocardial infarct]. 633 82

Three metabolic adaptive or compensatory mechanisms of heart failure were discussed: Adaptation of energy production and of energy availability in the myocardial cell. With increased myocardial oxygen demands this is achieved by a progressive displacement of the mass action ratio of the creatine phosphokinase reaction, so that pronounced changes in the creatine phosphate-ratio, related to myocardial oxygen consumption, are accompanied by only small changes in adenosine-5'-triphosphate adenosine-5'-diphosphate and hence in free energy of the adenine-nucleotide system. Adjustment of the oxygen availability by adaptation of the hemoglobin dissociation curve due to an increase in the erythrocyte content of 2, 3-diphosphoglycerate. This is accompanied by a swelling of erythrocytes as a consequence of an increase in the Gibbs-Donnan potential. In patients with congestive heart failure 2,3-diphosphoglycerate-synthesis is augmented due to respiratory alkalosis and increased concentrations of deoxygenated hemoglobin. Increase in the sympathetic drive of the heart due to increased net discharge of the neurotransmitter caused by reduced neuronal reuptake of norepinephrine. The diminished myocardial norepinephrine content in heart failure is due to the diminished neuronal uptake and to insufficient de novo catecholamine synthesis in the heart. Rather than tyrosine-hydroxylase the transformation of dopamine to norepinephrine seems to be the rate limiting step for catecholamine synthesis in heart failure.
 ...
PMID:Metabolic aspects of compensatory mechanisms in cardiac failure. 651 Jun 22

The following studies were carried out to examine energy metabolites and cardiac performance of the failing heart (hereditary cardiomyopathy) of the Syrian hamster (strain UM-X7.1) perfused either by normal or stress conditions, and to determine whether cyclical changes in energy-related metabolites occurred in the glucose-perfused hearts of both normal and heart failure animals. Hamster hearts from 250-day-old animals with moderate heart failure were removed and perfused either as nonworking hearts (Langendorff method, an afterload pressure of 90 mm Hg and 2.5 mM calcium in the perfusate) or as working hearts with stress conditions [an afterload of 110 mm Hg, high calcium concentrations in the perfusate (3.5 mM), and 10(-8) M isoproterenol]. Mechanical parameters (developed pressure and max dP/dt) and measurements of oxygen consumption indicated that both contractility and oxygen consumption had fallen 50% in myopathic hearts, compared with those of normal hamsters perfused with either of the two conditions. By means of a specially designed stimulator-triggered freeze clamp, hearts were terminated at systole and diastole, and tissue content of ATP, ADP, AMP, adenosine, phosphocreatine, creatine, pyruvate, lactate, and inorganic phosphate were analyzed. A 50% reduction in cardiac performance of the cardiomyopathic hamster hearts was associated with a corresponding reduction in systolic ATP, adenosine, and phosphocreatine values, while inorganic phosphate and lactate increased. With glucose as the sole substrate, the high energy phosphates, ATP and phosphocreatine, reached maximum values during diastole and minimum values during systole.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Energy levels at systole vs. diastole in normal hamster hearts vs. myopathic hamster hearts. 664 Aug 62

To identify any differences in inhibitory G protein (Gi) attributable to species or the cause of heart failure, we studied the changes in this protein in different animal models of heart failure: 1) different species; rats vs. hamsters (F1B) with cardiomyopathy induced by adriamycin (ADR) and 2) different etiologies; rats with ischemic heart failure (IHD) due to coronary artery ligation vs. rats with cardiomyopathy induced by ADR and F1B (20-week-old) hamsters with cardiomyopathy induced by ADR vs Syrian hamsters BIO 14.6 (40-week-old) with genetic cardiomyopathy, using Western blotting methods and ADP-ribosylation. We also sought to determine whether changes in the amount of Gi protein reflected the regulation of adenylate cyclase. The amount of immunodetectable Gi rose by 35% (p < 0.05) in ADR rats, 25% (p < 0.05) in ADR hamsters, 15% (p < 0.05) in IHD rats, and 28% (p < 0.05) in BIO 14.6 hamsters, as compared with control rats, F1B (20-week-old) hamsters, sham-operated control rats, and F1B (40-week-old) hamsters, respectively. Assessment of Gi by pertussis toxin-catalyzed ADP-ribosylation revealed increases in Gi of 24% (p < 0.05) in ADR rats and of 44% (p < 0.05) in BIO 14.6 hamsters, as compared with their respective controls. Gi function, as assayed by the acetylcholine-induced inhibition of adenylate cyclase, also increased. Thus, Gi protein appears to contribute to the changes in signal transduction in myocardium with heart failure.
 ...
PMID:Increased levels of inhibitory G protein in myocardium with heart failure. 769 38

In order to explain the attenuated sympathetic support during the development of heart failure, the status of beta-adrenergic mechanisms in the failing myocardium was assessed by employing cardiomyopathic hamsters (155-170 days old) at moderate degree of congestive heart failure. The norepinephrine turnover rate was increased but the norepinephrine content was decreased in cardiomyopathic hearts. The number and the affinity of beta receptors in the sarcolemmal preparations were not changed in these hearts at moderate stage of congestive heart failure. While the basal adenylyl cyclase activity was not altered in sarcolemma, the stimulation of enzyme activity by NaF, forskolin, Gpp(NH)p or epinephrine was depressed in hearts from these cardiomyopathic hamsters. Since G-proteins are involved in modifying the adenylyl cyclase activity, the functional and bioactivities as well as contents of both Gs and Gi proteins were determined in the cardiomyopathic heart sarcolemma. The functional stimulation of adenylyl cyclase by cholera toxin, which activates Gs proteins, was markedly depressed whereas that by Pertussis toxin, which inhibits Gi proteins, was markedly augmented in cardiomyopathic hearts. The cholera toxin and pertussis toxin catalyzed ADP-ribosylation was increased by 37 and 126%, respectively; this indicated increased bioactivities of both Gs and Gi proteins in experimental preparations. The immunoblot analysis suggested 74 and 124% increase in Gs and Gi contents in failing hearts, respectively. These results suggest that depressed adenylyl cyclase activation in cardiomyopathic hamsters may not only be due to increased content and bioactivity of Gi proteins but the functional uncoupling of Gs proteins from the adenylyl cyclase enzyme may also be involved at this stage of heart failure.
 ...
PMID:Alterations in G-proteins in congestive heart failure in cardiomyopathic (UM-X7.1) hamsters. 789 87

Several studies of phosphorus 31 (31P) magnetic resonance spectroscopy (MRS) have demonstrated the presence of skeletal muscle metabolic abnormalities during exercise in patients with chronic heart failure (CHF). We studied the contribution of these abnormalities to the limitation of exercise capacity in CHF. In 25 patients (age 57 +/- 2 years, left ventricular ejection fraction [LVEF] 28% +/- 1.6%, peak oxygen consumption (VO2) 16 +/- 1.2 ml/kg/mm) (mean +/- SEM), we studied the calf muscle at rest and during plantar flexion with 31P MRS. The phosphocreatine (PCr) depletion rate was significantly negatively correlated to peak VO2 (r = -0.62, p = 0.001) but not to LVEF. Muscle pH was correlated with the inorganic phosphorus (Pi)/PCr ratio (r = -0.69, p = 0.0001) and with the PCr/adenosine triphosphate beta (ATP beta) ratio (which negatively relates to adenosine diphosphate [ADP] concentration) (r = 0.65, p = 0.00001). Although muscle ATP (ATP/sum of phosphorus [sigma P] remained stable, in 8 patients ATP/sigma P decreased significantly (-15% +/- 4%, p = 0.0002). In this ATP-depleted group, peak VO2 was significantly lower than that of the nondepleted group and PCr depletion more rapid, whereas LVEF did not differ. Skeletal muscle metabolic abnormalities in CHF contribute markedly to the alteration of exercise capacity. Rapid PCr depletion and muscle acidosis are the most relevant abnormalities. ATP depletion and excessive increase in ADP during exercise may contribute further to exercise limitation specifically in patients with more marked CHF.
 ...
PMID:Contribution of specific skeletal muscle metabolic abnormalities to limitation of exercise capacity in patients with chronic heart failure: a phosphorus 31 nuclear magnetic resonance study. 794 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>